Focus on TGF-β signalling

Abstract

Transforming growth factor-b (TGF-b) is the index member of a large family of multifunctional growth factors. They were named originally for their ability to induce normal rat kidney fibroblasts to grow in soft agar in the presence of Epidermal Growth Factor (EGF) (De Larco & Todaro 1978, Roberts et al. 1981). There are 5 subtypes, all products of separate genes, three of which, TGF-b1, b2 and b3, have been shown to be expressed in mammalian ovarian cells (Derynck et al. 1988, Hernandez et al. 1990, Mulheron & Schomberg 1990). These factors are synthesized in inactive precursor forms that undergo cleavage to produce monomers, which can dimerize to 25 kDa forms through the conserved cysteine regions. The active regions of the TGF-b monomers share 98–100% identity. The isolation and cloning of inhibin and erythroid differentiation factor (subsequently called activin), and Mullerian inhibiting substance (MIS) led to the observation that these peptides are also members of the TGF-b superfamily. The family has grown to consist of more than 40 members (for a review see Chang et al. 2002), including the growth differentiation factors (GDFs) and bonemorphogenetic proteins (BMPs) (Fig. 1).Members of the family are related by sequence homology (30–40%) and conservation of the cysteine residues. Many also share a similar signal transduction mechanism involving serine–threonine kinase receptors with downstream Smad signalling pathways (for reviews see Miyazawa et al. 2002, Shi & Massague 2003, Lin et al. 2006). The concept that TGF-b superfamily members function as local regulators, either paracrine or autocrine, gained focus after a review on the topic was published by Sporn and Todaro (1980). Further to this, it had been realized that ‘there are events of gametogenesis and endocrine function .which do not necessarily have a direct relationship to the known hormonal milieu being determined by pituitary secretion rates and the afferent blood supply’ (Findlay & Risbridger 1987), supporting the concept of local regulation. It very quickly became apparent that many family members were acting as local regulators in reproductive tissues. In this issue of Reproduction, TGF-b signalling in reproductive tissues is reviewed. This focus issue begins with a chapter on the signal transduction systems that